A dual topology of STIM1 at the plasma membrane regulates calcium constitutive entry

A dual topology of STIM1 at the plasma membrane regulates calcium constitutive entry | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A dual topology of STIM1 at the plasma membrane regulates calcium constitutive entry Paul Buscaglia, NELIG LE GOUX, Patrice Hemon, Alix A.J Rouault, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7299685/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Mar, 2026 Read the published version in Cellular and Molecular Life Sciences → Version 1 posted 5 You are reading this latest preprint version Abstract STIM1, a type I transmembrane protein, was initially identified as a plasma membrane- localized protein with tumor growth suppressor activity, characterized by its N-terminal domain being extracellular (STIM1PM). The presence of STIM1PM at the plasma membrane (PM) is associated with N-glycosylation, which facilitates its trafficking and stability at the PM. Subsequently, STIM1PM has been recognized as a critical component in the regulation of store-independent Ca2+ entry pathways, including arachidonic acid-regulated Ca2+ (ARC) channels and constitutive Ca2+ entry (CCE). In this study, we demonstrate that STIM1PM exhibits dual topology at the PM, presenting both the expected type I orientation and an alternative type II orientation. We found that both orientations of STIM1PM contribute to the regulation of CCE. As anticipated, the N-glycosylation state of STIM1PM influences its presence at the PM and its dual topology. Our findings reveal that STIM1PM exists with dual topology and begin to elucidate the mechanisms underlying this multiple orientation. Dual topology STIM1PM constitutive Ca2+ entry antiparallel dimers regulation plasma membrane Full Text Cite Share Download PDF Status: Published Journal Publication published 06 Mar, 2026 Read the published version in Cellular and Molecular Life Sciences → Version 1 posted Editorial decision: Major Revision 14 Sep, 2025 Reviewers agreed at journal 15 Aug, 2025 Reviewers invited by journal 12 Aug, 2025 Editor assigned by journal 06 Aug, 2025 First submitted to journal 06 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7299685","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":499146053,"identity":"906b18ef-5fb0-4f08-9e1c-cf54e9d2b762","order_by":0,"name":"Paul Buscaglia","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Paul","middleName":"","lastName":"Buscaglia","suffix":""},{"id":499146054,"identity":"d4ad5cb4-18ec-4161-88f3-49a15899c398","order_by":1,"name":"NELIG LE GOUX","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBklEQVRIie3RPWrDMBTA8ScE8SI6P+iHryBjSBPI3mvYFDq5U8Bki0JBWQxZc4xmyRwjaBfjOeChhF5AhVI8VrLJUpDJ2EF/kHjLD0kIwOf7l1FxAJj0szbrqh+TAUIswX7cmm10CYEzoewSch+sVuU34F34UIyvZ/k+lUBPmsgnJ5kWpVA3gHFUVXGc1Y0hoxiJzJyEH1OhEDDdbbPo81laAmMgcuEmH6eOLA3hatqR4GeYHIkoNWASojmFdITZUwYuVpmLAcfolb3No6JuYknZHJPa/Xz+rtRXu5iF4fplj23e3G6C9U7r/NFJbJRxYw92tJ9CYfgjbaQ1WyjOxOfz+Xx/+gWNxVLpJlssSgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0002-5904-3606","institution":"Queen Mary University of London","correspondingAuthor":true,"prefix":"","firstName":"NELIG","middleName":"LE","lastName":"GOUX","suffix":""},{"id":499146055,"identity":"69e8a987-69e9-4a1c-86d7-867904d9bfc0","order_by":2,"name":"Patrice Hemon","email":"","orcid":"","institution":"Universite de Brest: Universite de Bretagne Occidentale","correspondingAuthor":false,"prefix":"","firstName":"Patrice","middleName":"","lastName":"Hemon","suffix":""},{"id":499146056,"identity":"673cd7c2-338c-4a55-9f8a-c0b59eb12397","order_by":3,"name":"Alix A.J Rouault","email":"","orcid":"","institution":"The University of Iowa","correspondingAuthor":false,"prefix":"","firstName":"Alix","middleName":"A.J","lastName":"Rouault","suffix":""},{"id":499146057,"identity":"e8a6aa8c-bf9a-4e7f-ac2a-977d8e532322","order_by":4,"name":"Julien A. Sebag","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Julien","middleName":"A.","lastName":"Sebag","suffix":""},{"id":499146058,"identity":"3309382d-6d1f-46be-b4df-469228a4e4f0","order_by":5,"name":"Olivier Mignen","email":"","orcid":"","institution":"Bretagne Occidentale University: Universite de Bretagne Occidentale","correspondingAuthor":false,"prefix":"","firstName":"Olivier","middleName":"","lastName":"Mignen","suffix":""}],"badges":[],"createdAt":"2025-08-05 10:50:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7299685/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7299685/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00018-026-06141-0","type":"published","date":"2026-03-06T15:59:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":104250844,"identity":"a01e62ca-3571-4847-bc8c-7542357ff7c8","added_by":"auto","created_at":"2026-03-09 16:09:56","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2087957,"visible":true,"origin":"","legend":"","description":"","filename":"STIM1DualTopologyTextCMLSSubmission1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7299685/v1_covered_22c6369a-9a0a-4576-bfef-169e7c9264ed.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eA dual topology of STIM1 at the plasma membrane regulates calcium constitutive entry\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-life-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"life","sideBox":"Learn more about [Cellular and Molecular Life Sciences](https://link.springer.com/journal/18)","snPcode":"18","submissionUrl":"https://www.editorialmanager.com/life/default2.aspx","title":"Cellular and Molecular Life Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Dual topology, STIM1PM, constitutive Ca2+ entry, antiparallel dimers, regulation, plasma membrane","lastPublishedDoi":"10.21203/rs.3.rs-7299685/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7299685/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"STIM1, a type I transmembrane protein, was initially identified as a plasma membrane- localized protein with tumor growth suppressor activity, characterized by its N-terminal domain being extracellular (STIM1PM). The presence of STIM1PM at the plasma membrane (PM) is associated with N-glycosylation, which facilitates its trafficking and stability at the PM. Subsequently, STIM1PM has been recognized as a critical component in the regulation of store-independent Ca2+ entry pathways, including arachidonic acid-regulated Ca2+ (ARC) channels and constitutive Ca2+ entry (CCE). In this study, we demonstrate that STIM1PM exhibits dual topology at the PM, presenting both the expected type I orientation and an alternative type II orientation. We found that both orientations of STIM1PM contribute to the regulation of CCE. As anticipated, the N-glycosylation state of STIM1PM influences its presence at the PM and its dual topology. Our findings reveal that STIM1PM exists with dual topology and begin to elucidate the mechanisms underlying this multiple orientation.","manuscriptTitle":"A dual topology of STIM1 at the plasma membrane regulates calcium constitutive entry","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-19 16:57:00","doi":"10.21203/rs.3.rs-7299685/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2025-09-14T04:19:16+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-08-15T12:39:05+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-12T05:11:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-06T15:17:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cellular and Molecular Life Sciences","date":"2025-08-06T05:39:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-life-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"life","sideBox":"Learn more about [Cellular and Molecular Life Sciences](https://link.springer.com/journal/18)","snPcode":"18","submissionUrl":"https://www.editorialmanager.com/life/default2.aspx","title":"Cellular and Molecular Life Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"87dc0c67-f158-4f8e-89a6-245eaeb85694","owner":[],"postedDate":"August 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-09T16:06:07+00:00","versionOfRecord":{"articleIdentity":"rs-7299685","link":"https://doi.org/10.1007/s00018-026-06141-0","journal":{"identity":"cellular-and-molecular-life-sciences","isVorOnly":false,"title":"Cellular and Molecular Life Sciences"},"publishedOn":"2026-03-06 15:59:06","publishedOnDateReadable":"March 6th, 2026"},"versionCreatedAt":"2025-08-19 16:57:00","video":"","vorDoi":"10.1007/s00018-026-06141-0","vorDoiUrl":"https://doi.org/10.1007/s00018-026-06141-0","workflowStages":[]},"version":"v1","identity":"rs-7299685","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7299685","identity":"rs-7299685","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}